There is increasing evidence that certain synthetic and natural chemicals may act as agonists or antagonists to estrogens or androgens and may interfere in multiple ways with the action of thyroid hormones; such compounds can be called endocrine disruptors. For example, endocrine disruptors can mimic or block chemicals naturally found in the body, thereby altering the body's ability to produce hormones, interfering with the ways hormones travel through the body, and altering the concentration of hormones reaching hormone receptors.
Endocrine disruptors and natural estrogens share a common mechanism of action. In normal cases, estrogenic activity is produced by binding natural estrogen to an estrogen receptor (ER) within the nucleus of the cell, followed by transcriptional activation of these occupied ERs. When endocrine disruptors are present, normal estrogenic activity is supplanted when endocrine disruptors bind an ER, causing transcriptional activation of the ER even though no natural estrogen is present. Similarly, antiestrogenic activity is produced by endocrine disruptors which bind to ERs but which do not subsequently activate the occupied ER as well as natural estrogen. Finally, selective estrogen receptor modulators (SERMs) bind to ERs, but subsequently activate cellular responses that differ from those activated by the natural estrogens. In general, all but a very small number of molecules that bind to ERs produce some activation of the receptors, as either estrogens or as SERMs.
Examples of suspected endocrine disruptors may include, for example: Dioxin, Polychlorinated biphenyls (PCBs), Polybrominated biphenyls (PBBs), Hexachlorobenzene (HcB), Pentachlorophenol (PCP), 2,4,5-Trichlorophenoxy acetic acid (2,4,5-T), 2,4-Dichlorophenoxyacetic acid (2,4-D), alkylphenols such as Nonylphenol or Octylphenol, Bisphenol A, Di-2-ethylhexyl phthalate (DEHP), Butylbenzyl phthalate (BBP), Di-n-butyl phthalate (DBP) Dicyclohexyl phthalate (DCHP), Diethyl phthalate (DEP), Benzo (a) pyrene, 2,4-Dichlorophenol (2,4-DPC), Di(2-ethylhexyl)adipate, Benzophenone, P-Nitrotoluene, 4-Nitrotoluene, Octachlorostyrene, Di-n-pentyl phthalate (DPP), Dihexyl phthalate (DHP), Dipropyl phthalate (DprP), Styrene dimers and trimers, N-Butyl benzene, Estradiol, Diethlhexyl adipate, Diethlhexyl adipate (DOA), trans-cholordane, cis-cholordane, p-(1,1,3,3-Tetramethlbutyl)phenol (TMBP), and (2,4-Dichlorophenoxy)acetic acid (2,4-PA).
Alkylphenols and products produced by them have come under increased scrutiny due to their association as potential endocrine disruptive components. This is namely due to the weak estrogenic activity of base alkylphenol as well as degradation intermediates of the alkylphenol products. Alkylphenols commercially are used in herbicides, gasoline additives, dyestuffs, polymer additives, surfactants, lubricating oil additives and antioxidants. In the recent years, alkylphenol alkoxylates, such as ethoxylated nonylphenol, have been criticized for having poor biodegradability, high aquatic toxicity of the by-products of the biodegradation of the phenol portion, and there is an increasing concern that these chemicals may act as endocrine disrupters. Some studies have shown there to be links between alkylphenols and declining sperm count in human males and there is evidence that alkylphenols may harmfully disrupt the activity of human estrogen and androgen receptors. Specifically, Routledge et al., Structural features of alkylphenolic chemicals associated with estrogenic activity, J Biol Chem., 1997 Feb. 7; 272(6):3280-8, compared different alkylphenols estrogenic activity in an estrogen-inducible strain of yeast comparing the assays with 17β-estradiol. The results indicated that optimal estrogenic activity requires a single branched alkyl group composed of between 6 and 8 carbon atoms located at the para position on an otherwise unhindered phenol ring with 4-tert-octylphenol (8 carbons also named 4-(1,1,3,3-Tetramethyl-butyl)-phenol)) having the highest activity. Routledge et al., tested various alkylphenols in the assay and indicated that alkyl chain length, degree of branching, location on the ring, and degree of isomeric heterogeneity affect the binding efficiency but was not able to draw a structure activity conclusion. For example, Routledge et al., stated that the p-nonylphenol as determined by high resolution gas chromatographic analysis identified 22 para-isomers speculating that all isomers would not have similar activity without elucidating the active species. Interestingly, Tabria et al., Structural requirements of para-alkylphenols to bind to estrogen receptor, Eur. J. Biochem. 262, 240-245 (1999) found that when using human estrogen receptors, the receptor binding of alkylphenols was maximized when the number of alkyl carbons was nine carbon atoms. Tabria et al., noted that branched chain nonylphenol, mixture of isomers (commercially available and which did not contain any n-nonylphenol) was almost as active as n-nonylphenol.
Nonylphenol ethoxylate and octylphenol ethyoxylate are widely used as nonioionic surfactants. Concern over the environmental and health impact of these alkoxylated alkylphenols has led to governmental restriction on the use of these surfactants in Europe, as well as voluntary industrial restrictions in the United States. Many industries have attempted to replace these preferred alkoxylated alkylphenol surfactants with alkoxylated linear and branched alkyl primary and secondary alcohols, but have encountered problems with odor, performance, formulating, and increased costs. Although the predominate focus has been on the alkylphenol ethoxylates and the potential problems associated these compounds and primarily with the degradation by-products, there remains a need to review other components to select combinations that have similar or improved performance benefits with reduced negative impacts.
Nonylphenol and dodecylphenol can be produced by the following steps: propylene oligomerization and separation of propylene trimer and tetramer, and phenol alkylation with propylene trimer and separation of nonylphenol, or phenol alkylation with propylene tetramer and separation of dodecylphenol. Tetrapropenyl phenol prepared from propylene tetramer has been widely used in the lubricant additive industry. Tetramer is a cost effective olefin to manufacture; the highly branched chain of 10 to 15 carbons with high degree of methyl branching imparts exceptional oil solubility and compatibility with other oil soluble lubricant additive components. Dodecylphenol derived from propylene tetramer is primarily used as in an intermediate in the production of additives for lubricating oils, commonly sulfurized alkyl phenate detergents. To a lesser degree, these branched phenate detergents have employed some degree of linear olefin.
U.S. Pat. No. 3,036,971 discloses preparing detergent dispersant additives based on sulfurized alkylphenates of high basicity alkaline earth metals, wherein the alkyl group is derived from propylene tetramer. These additives are prepared by sulfurization of an alkylphenol, neutralization of the sulfurized alkylphenol with an alkaline earth base, and then super-alkalization by carbonation of the alkaline earth base dispersed in the sulfurized alkylphenate. Similar metal overbased sulfurized alkylphenate compositions are described for example in U.S. Pat. Nos. 3,178,368; 3,367,867; and 4,744,921, with the latter disclosing phenates derived from a mixture of linear and branched alkylphenols using a sulfurization catalyst.
U.S. Pat. No. 5,320,763 discloses a metal overbased sulfurized alkylphenate derived from alkylphenols enriched in C10 to C16 alkyl substituents attached to the phenol ring in the “end” position. Similarly, U.S. Pat. Nos. 5,318,710 and 5,320,762 are directed to overbased sulfurized alkylphenates derived from alkylphenols from internal olefins, and thus are enriched in middle and skewed attachment. In all of these disclosures, the alkyl groups may contain a large portion of trisubstituted and tetrasubstituted carbon atoms and thus have a large degree of quaternary carbons.
U.S. Pat. No. 5,244,588 discloses a process for producing overbased sulfurized alkaline earth metal phenates having a base value of 240 to 330 mg KOH/g, which comprises reacting alkylphenol, prepared from C14-28 straight-chain alkene and phenol, with sulfur, alkaline earth metal compound and dihydric alcohol to prepare a reaction mixture, then distilling off water and dihydric alcohol from the reaction mixture, subsequently treating the reaction mixture with carbon dioxide to give basic sulfurized alkaline earth metal phenates, and further subjecting to overbasification using a solvent containing aromatic hydrocarbon and at least one of monohydric alcohol and water.